EP0357792B1 - Verfahren zur herstellung von pyridin-2,3-dicarbonsäure-verbindungen - Google Patents

Verfahren zur herstellung von pyridin-2,3-dicarbonsäure-verbindungen Download PDF

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Publication number
EP0357792B1
EP0357792B1 EP89903222A EP89903222A EP0357792B1 EP 0357792 B1 EP0357792 B1 EP 0357792B1 EP 89903222 A EP89903222 A EP 89903222A EP 89903222 A EP89903222 A EP 89903222A EP 0357792 B1 EP0357792 B1 EP 0357792B1
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acid
compound
formula
reaction
dicarboxylic acid
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EP0357792A1 (de
EP0357792A4 (en
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Takaharu Yamashita
Mitsuhiro Kodama
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Sugai Chemical Industry Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3

Definitions

  • This invention relates to a process for preparing pyridine-2,3-dicarboxylic acid compounds. More particularly, it relates to a process for preparing pyridine-2,3-dicarboxylic acid compounds which are useful as an intermediate for manufacturing agricultural chemicals and pharmaceuticals.
  • the above method (1) not only has many reaction processes but also requires drastic oxidation with nitric acid, and involves possible hazards. Also, the pyridine-2,3-dicarboxylic acids, which are apt to cause decarboxylation, result in low yields by the oxidation with nitric acid, and, in addition, produce a large quantity of acidic waste liquid. Thus, the method (1) is not suited to the industrial manufacture of pyridine-2,3-dicarboxylic acids.
  • the methods (2) and (3) mentioned above have many reaction processes leading to decreased total yields, and require the use of expensive starting materials. Particularly, they require elimination process of the substituted amino group in the intermediate. This decreases the yield and becomes a problem on resource saving. Therefore, it is difficult to manufacture pyridine-2,3-dicarboxylic acid derivatives industrially by the method (2) or (3).
  • a process for preparing pyridine-2,3-dicarboxylic acid compounds of the invention is a process for preparing pyridine-2,3-dicarboxylic acid compounds represented by the following formula (1). wherein R1 and R2 are, identical or different, a lower alkyl group, and R3 is a hydrogen atom or a lower alkyl group, which comprises reacting a compound of the following formula (2): wherein R1 and R2 are the same as defined above and M is an alkali metal, with an acid and a halogenating agent to give a compound of the following formula (3): wherein R1 and R2 are the same as defined above and X is a halogen atom, and then reacting the compound of the above formula (3) with the compound of the following formula (4): wherein R3 is the same as defined above, and ammonia, wherein the compound of formula (3) resulting from the reaction of the compound of formula (2) with an acid and a halogenating agent is reacted without isolation with the compound of formula (4) and ammonia
  • EP-A-0 274 379 discloses a process for preparing pyridin-2,3-dicarboxylic acid compounds by reacting the compound having the above mentioned formula (3) with a compound having the above formula (4) and ammonia.
  • examples of the lower alkyl groups for R1, R2, and R3 include, for example, straight or branched chain alkyl groups having 1 to 8 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary-butyl, pentyl, hexyl, heptyl, octyl, 2-ethylhexyl group, and the like.
  • alkali metal for M examples include, for example, sodium, potassium, and the like.
  • halogen atom for X examples include, for example, fluorine atom, chlorine atom, bromine atom, and the like.
  • Examples of the compound of the formula (2) include, for example, dimethyl oxalacetate sodium salt, diethyl oxalacetate sodium salt, methyl ethyl oxalacetate sodium salt, dimethyl oxalacetate potassium salt, diethyl oxalacetate potassium salt, di-tertiary-butyl oxalacetate sodium salt, di-tertiary-butyl oxalacetate potassium salt, dipropyl oxalacetate sodium salt, dipropyl oxalacetate potassium salt, and the like.
  • Examples of the compound of the formula (3) include, for example, dimethyl ⁇ -chlorooxalacetate, diethyl ⁇ -chlorooxalacetate, methyl ethyl ⁇ -chlorooxalacetate, dimethyl ⁇ -bromooxalacetate, diethyl ⁇ -bromooxalacetate, di-tertiary-butyl ⁇ -chlorooxalacetate, dipropyl ⁇ -chlorooxalacetate, dipropyl ⁇ -fluorooxalacetate, and the like.
  • Examples of the compound of the formula (4) include, for example, acrolein, 2-methyl-2-propenal, 2-ethyl-2-propenal, 2-propyl-2-propenal, 2-isopropyl-2-propenal, 2-butyl-2-propenal, 2-pentyl-2-propenal, 2-hexyl-2-propenal, 2-heptyl-2-propenal, 2-octyl-2-propenal, and the like.
  • R1, R2, R3, X, and M are the same as defined before.
  • the reaction of the reaction scheme 1 comprises a step which obtains the compound of the formula (3) by reacting the compound of the formula (2), an acid and a halogenating agent (step 1), and a step which obtains the compound of the formula (1) by reacting the compound of the formula (3) obtained above, the compound of the formula (4) and ammonia (step 2).
  • examples of the acid used in the step include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid, and organic acids including lower alkanoic acids such as formic acid, oxalic acid, acetic acid, and propionic acid, and sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and toluenesulfonic acid.
  • examples of the halogenating agent include sulfuryl chloride, bromine, and chlorine.
  • This reaction can be carried out by either process, in which the compound of the formula (2) is allowed to react with the halogenating agent in the presence of the acid or in which the compound of the formula (2) is treated with the acid and then allowed to react with the halogenating agent .
  • organic solvent Any organic solvent may be used unless the solvent affects the reaction, but aprotic solvents including aromatic hydrocarbons such as toluene and benzene, and halogenated hydrocarbons such as chloroform, 1,2-dichloroethane and carbon tetrachloride are desirable.
  • aromatic hydrocarbons such as toluene and benzene
  • halogenated hydrocarbons such as chloroform, 1,2-dichloroethane and carbon tetrachloride are desirable.
  • reaction temperature at which reaction of the compound of the formula (2) or its acid-treated compound with the halogenating agent takes place is not particularly specified, but, in general, the reaction is carried out at 0 - 100°C, and preferably at 1 - 50°C. The reaction is completed in 30 minutes to 10 hours, generally 1 to 5 hours.
  • the molar ratio of compound of the formula (2) to the halogenating agent can be varied widely, but in general it is desirable to use 0.6 - 1.5 mols, preferably 1 - 1.3 mols of the halogenating agent to 1 mol of the compound of the formula (2).
  • the acid is used at least an equimolar amount, and preferably slightly in excess to the compound of the formula (2).
  • Combinations of the above-mentioned acid, organic solvent, and halogenating agent are optional, but it is most desirable to combine alkanoic acids, in particular, formic acid as acid, and halogenated hydrocarbons, in particular, chloroform as organic solvent, and sulfuryl chloride as halogenating agent.
  • the compound of the formula (3) which is obtained in this way can be used for the reaction of step 2 without isolation or after isolation and purification by a manner such as distillation and column chromatography.
  • the reaction of the step 2 is carried out to obtain the compound of the formula (1) by allowing the compound of the formula (3) obtained above to react with the compound of the formula (4) and ammonia.
  • the reaction is carried out under the condition free from solvent or in the organic solvent.
  • Any organic solvent which does not affect the reaction can be used irrespective of polar, nonpolar, protic, or aprotic.
  • solvents include alcohol such as methanol, ethanol, isopropyl alcohol, and butanol; halogenated hydrocarbons such as chloroform, 1,2-dichloroethane, and carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene, o-dichlorobenzene, and nitrobenzene; ethers such as dimethyl ether, diethyl ether, dibutyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, and dibenzyl ether; esters such as methyl acetate and ethyl acetate; apro
  • Reaction temperature is not particularly specified and the reaction can be carried out at various temperatures; for example, temperature range from 10 to 200°C; in particular, 35 - 130°C is more desirable. It is desirable to carry out the reaction under pressure, in particular, with ammonia pressurized at 0.3 - 2.5 kg/cm2. The reaction is completed in 30 minutes to 24 hours, in general in about 1 - 10 hours.
  • the compounds of the formulae (3) and (4) can be used at the proper molar ratio; for example, 0.8 - 1.5 mols, particularly 1.0 - 1.2 mols of the compound of the formula (4) to 1.0 mol of the compound of the formula (3) is used desirably.
  • Ammonia is used usually in excess to the compounds of the formulae (3) and (4).
  • the above-mentioned reaction is preferably carried out in the presence of ammonium salt such as ammonium carbonate, ammonium chloride, ammonium sulfate, ammonium nitrate, ammonium phosphate, and ammonium acetate.
  • ammonium salt such as ammonium carbonate, ammonium chloride, ammonium sulfate, ammonium nitrate, ammonium phosphate, and ammonium acetate.
  • ammonium salt can be used in an adequate amount, but it is desirable to use 0.05 - 1.0 mol of the ammonium salt to 1 mol of the compound of the formula (4).
  • the ester compound of the formula (1) which is obtained through the process of this invention can be converted to corresponding pyridine-2,3-dicarboxylic acid compound by hydrolysis using the known method.
  • the hydrolysis can be carried out in water or aqueous solvent by the conventional method using basic compounds such as alkali metal hydroxides including sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; and alkali metal hydrogen carbonates such as sodium hydrogencarbonate and potassium hydrogencarbonate, however, alkali metal hydroxides are desirable to achieve completely the reaction.
  • the hydrolysis is carried out at room temperature to 150°C, preferably at 40 - 100°C and completed usually in about 1 - 24 hours.
  • the desired carboxylic acid compounds can be obtained by subjecting the carboxylic acid salts produced by the above hydrolysis to acid precipitation with a mineral acid such as hydrochloric acid, sulfuric acid, nitric acid, or phosphoric acid at 20 - 60°C.
  • a mineral acid such as hydrochloric acid, sulfuric acid, nitric acid, or phosphoric acid at 20 - 60°C.
  • the compound of the formula (3) can be obtained in a high yield in contrast to the above method, resulting in improvement of the yield of the compound of the formula (1).
  • Pyridine-2,3-dicarboxylic acid compounds obtained by the process of this invention is useful as the intermediate for synthesizing various compounds such as agricultural chemicals and pharmaceuticals.
  • the process to prepare pyridine-2,3-dicarboxylic acid compounds according to the invention can produce the pyridine-2,3-dicarboxylic acid compounds with less steps and in high yield.
  • it has a feature to carry out the reaction without isolating the intermediate.
  • the process permits the use of inexpensive readily available starting material, can be performed in safety because the reaction proceeds under the mild conditions, and realizes easy disposal of waste liquid.
  • the pyridine-2,3-dicarboxylic acid compounds can be manufactured in the industrial scale.
  • this filtrate and 17.7 g of 2-ethyl-2-propenal (0.21 mol) were mixed in a 100-ml glass autoclave. After closing the autoclave, the internal temperature was raised to 110°C, and ammonia gas was introduced until the ammonia partial pressure reached 0.5 to 2.5 kg/cm2, and the reaction was continued for 5 hours. The content was cooled to room temperature, and the insoluble matter was filtered off. The filtrate was concentrated, and the residue was distilled, and 5-ethyl-2,3-diethoxycarbonylpyridine (bp2: 151 to 152°C) was obtained in a yield of 62.4% based on the charged oxalacetic acid diethyl ester sodium salt.
  • this chloroform solution 5.6 kg of 2-ethyl-2-propenal (66.6 mols) and 1.0 kg of ammonium acetate (13.0 mols) were mixed in a 100-liter glass autoclave. After closing it, the internal temperature was raised up to 60°C to discharge the air in the vapor phase, and the temperature was further raised to 105°C, and ammonia gas was introduced thereto until the internal pressure reached 3.5 to 6.0 kg/cm2 and the reaction was conducted for 8 hours. After cooling the content to room temperature, 16 liters of water was added to dissolve the inorganic salt produced by the reaction to separate into the chloroform layer and water layer. The separated chloroform layer was concentrated, and 17.4 kg of brown oily matter was obtained.
  • the filtrate was kept at 10 to 20°C, and 17 g of sulfuryl chloride (0.126 mol) was added dropwise over a period of 1 hour, and the reaction was continued for 5 hours at 40°C. After cooling the content to room temperature, it was degassed in vacuo. The obtained solution was analyzed by gas chromatography, and ⁇ -chlorooxalacetic acid diethyl ester was obtained in a yield of 64% based on the charged oxalacetic acid diethyl ester sodium salt.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)

Claims (5)

  1. Verfahren zur Herstellung von Pyridin-2,3-dicarbonsäure-Verbindungen der Formel (1):
    Figure imgb0011
     worin R¹ und R², gleich oder verschieden, eine Niederalkyl-Gruppe sind und R³ ein Wasserstoffatom oder eine Niederalkyl-Gruppe ist,
    welches umfaßt:
    Umsetzung der Verbindung der Formel (2):
    Figure imgb0012
     worin R¹ und R² wie oben definiert sind und M ein Alkalimetall ist, mit einer Säure und einem Halogenierungsmittel zur Bildung der Verbindung der Formel (3):
    Figure imgb0013
     worin R¹ und R² wie oben definiert sind und X ein Halogenatom ist, und dann Umsetzung des resultierenden Produkts mit der Verbindung der Formel (4):
    Figure imgb0014
     worin R³ wie oben definiert ist, und Ammoniak, wobei die Verbindung der Formel (3), die aus der Reaktion der Verbindung der Formel (2) mit einer Säure und einem Halogenierungsmittel resultiert, ohne Isolierung mit der Verbindung der Formel (4) und Ammoniak umgesetzt wird.
  2. Verfahren zur Herstellung von Pyridin-2,3-dicarbonsäure-Verbindungen gemäß Anspruch 1, worin die Reaktion der Verbindung der Formel (2) mit einem Halogenierungsmittel in einem aprotischen organischen Lösungsmittel und in Gegenwart einer Säure bei einer Temperatur von 0 bis 100°C ausgeführt wird.
  3. Verfahren zur Herstellung von Pyridin-2,3-dicarbonsäure-Verbindungen gemäß Anspruch 2, worin das aprotische organische Lösungsmittel Chloroform ist, die Säure Ameisensäure ist und das Halogenierungsmittel Sulfurylchlorid ist.
  4. Verfahren zur Herstellung von Pyridin-2,3-dicarbonsäure-Verbindungen gemäß Anspruch 3, worin die Reaktion der Verbindungen der Formeln (3) und (4) und Ammoniak unter Druck und bei einer Temperatur von 10 bis 200°C ausgeführt wird.
  5. Verfahren zur Herstellung von Pyridin-2,3-dicarbonsäure-Verbindungen gemäß einem der Ansprüche 1 bis 4, worin die Reaktion der Verbindungen der Formeln (3) und (4) und Ammoniak in Gegenwart eines Ammoniumsalzes ausgeführt wird.
EP89903222A 1988-03-18 1989-03-17 Verfahren zur herstellung von pyridin-2,3-dicarbonsäure-verbindungen Expired - Lifetime EP0357792B1 (de)

Priority Applications (1)

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EP93116799A EP0588372B1 (de) 1988-03-18 1989-03-17 Verfahren zur Herstellung von Pyridin-2,3-Dicarbonsäure-Verbindungen

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JP66772/88 1988-03-18
JP6677288 1988-03-18
PCT/JP1989/000288 WO1989008645A1 (en) 1988-03-18 1989-03-17 Process for preparing pyridine-2,3-dicarboxylic acid compounds

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EP93116799A Division EP0588372B1 (de) 1988-03-18 1989-03-17 Verfahren zur Herstellung von Pyridin-2,3-Dicarbonsäure-Verbindungen

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EP0357792B1 true EP0357792B1 (de) 1995-06-28

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US5276157A (en) * 1991-12-20 1994-01-04 American Cyanamid Company Process for the purification of 2,3-pyridine and quinolinedicarboxylic acid diester compounds
US5925764A (en) * 1998-06-15 1999-07-20 Wu; Wen-Xue Process and intermediated for the manufacture of pyridine-2, 3-dicarboxylate compounds

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US4723011A (en) * 1985-10-28 1988-02-02 American Cyanamid Company Preparation of substituted and disubstituted-pyridine-2,3-dicarboxylate esters
EP0274379B1 (de) * 1987-01-06 1993-06-30 Sugai Chemical Industry Co., Ltd. Verfahren zur Herstellung von Pyridin-2,3-dicarboxylsäure-Verbindungen
JP2561500B2 (ja) * 1987-01-06 1996-12-11 スガイ化学工業株式会社 ピリジン−２，３−ジカルボン酸誘導体の製造方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
of rotenone and its derivatives. part XVI. The synthesis of abutic acid and itsanalogues" *
THE JOURNAL OF THE AMERICAN SOCIETY, vol. 72, September-December 150, pages 5221-5225; L.H. CONOVER et al.: "Thiazole analogs of pyridoxine" *

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EP0357792A1 (de) 1990-03-14
DE68923232D1 (de) 1995-08-03
DE68923232T2 (de) 1996-01-04
WO1989008645A1 (en) 1989-09-21
EP0357792A4 (en) 1990-09-05
DE68929429T2 (de) 2003-06-18
DE68929429D1 (de) 2002-11-07
EP0588372A1 (de) 1994-03-23
EP0588372B1 (de) 2002-10-02

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